This application for renewal of our longstanding Program Project is based on a highly focused, integrated and interactive effort to examine the hypothesis that mitochondrial antioxidants are capable of resisting age-related disease and improving health and function in multiple organ systems in mammals. This builds on past progress, including observations that mice overexpressing mitochondrially targeted catalase have extended lifespan, improved cardiac, and muscle health and resistance to epithelial cancers. We therefore have developed an increasing focus on health and healthspan, including study of acute models of decline in organ function that can serve as surrogate assays for similar disorders in aging. In this Program Project we propose four Projects to apply this approach to disorders of aging in which mitochondrial reactive oxygen species (ROS) and ROS-induced damage play an important role: 1) Mitochondrial ROS and cardiac aging;2) Mitochondrial ROS and neurodegenerative disease;3) Mitochondrial ROS and protection from epithelial cancers in aging;4) Mitochondrial-targeted antioxidants, aging and AZT in skeletal muscle dysfunction. The Projects are supported by four Cores: 1) Administrative;2) Mouse pathobiology;3) Proteomics;4) Mitochondrial protective chemistry. In each of these Projects and Cores we seek to understand the mechanisms underlying the role of mitochondrial ROS in aging and healthspan, as well as pursuing the translational goal of identifying mitochondrial protective drugs to deliver these healthspan benefits to humans. PUBLIC HEALTH RELEVANCE: By working with mouse models of protection from mitochondrial oxidation and damage, and translating from genetic models to pharmacologic agents, this Program Project hopes to deliver significant health benefits in muscle, heart, brain, and cancer protection to the aging human population. REVIEW OF INDIVUDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATION CORE;Dr. Peter S. Rabinovitch, Core Leader (CL) DESCRIPTION (provided by applicant): Specific Aims 1. Provision of an organizational structure to expedite research and promote communication between Program Project components and investigators. 2. Monitor and regularly review the quality and progress of research 3. Insure adherence to rigorous statistical considerations in experimental design and data analysis 4. Management of fiscal components of the Program Project including reallocation of funds to optimize overall function. 5. Short-range and long-range planning for the enhancement and integration of Program Project facilities. 6. Provide data sharing and data dissemination facilities for the P01. PUBLIC HEALTH RELEVANCE: Statistical rigor in experimental design and data analysis is an important administrative coordinating goal to ensure that all experimental designs meet the highest statistical rigor. Ensuring that all Cores and Projects are coordinated is the main goal of this Core.